Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis.

Patel P, Julien JP, Kriz J - Neurotherapeutics (2015)

Bottom Line:
Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality.These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

ABSTRACTApproximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that Withaferin A (WA), an inhibitor of nuclear factor-kappa B activity, was efficient in reducing disease phenotype in a TAR DNA binding protein 43 transgenic mouse model of ALS. These findings led us to test WA in mice from 2 transgenic lines expressing different ALS-linked SOD1 mutations, SOD1(G93A) and SOD1(G37R). Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice. The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality. Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter. These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

Mentions:
We examined the effect of WA in transgenic mice overexpressing SOD1G93A or SOD1G37R mutants. As described in details in the “Materials and Methods”, starting at postnatal day 40, the SOD1G93A mice were treated with WA twice a week (4 mg/kg i.p.). The mice received continuous treatment until the end stage of disease. A similar therapeutic protocol was applied for the treatment of the SOD1G37R mice. Mice were injected with the same dose, starting at 9 months (early stage of disease) until the end stage of disease. Treatment with WA significantly extended the survival of SOD1G93A mice. Mean survival of vehicle-treated SOD1G93A mice was 145 days (n =15), whereas treatment with WA increased the lifespan of SOD1G93A mice to 153 days (n =16) (p <0.05, a difference of 8 days; Fig. 1A). In the mouse model with slowly progressing disease—the SOD1G37R model—the mean survival of WA-treated SOD1G37R mice was 397 days (n =8) compared with controls (379 days; n =8) (p <0.01, a difference of 18 days; Fig. 1B). Furthermore, treatment with WA significantly delayed the loss of motor function observed in the motor function tests and prevented the loss of body weight (Fig. 1C, D).Fig. 1

Mentions:
We examined the effect of WA in transgenic mice overexpressing SOD1G93A or SOD1G37R mutants. As described in details in the “Materials and Methods”, starting at postnatal day 40, the SOD1G93A mice were treated with WA twice a week (4 mg/kg i.p.). The mice received continuous treatment until the end stage of disease. A similar therapeutic protocol was applied for the treatment of the SOD1G37R mice. Mice were injected with the same dose, starting at 9 months (early stage of disease) until the end stage of disease. Treatment with WA significantly extended the survival of SOD1G93A mice. Mean survival of vehicle-treated SOD1G93A mice was 145 days (n =15), whereas treatment with WA increased the lifespan of SOD1G93A mice to 153 days (n =16) (p <0.05, a difference of 8 days; Fig. 1A). In the mouse model with slowly progressing disease—the SOD1G37R model—the mean survival of WA-treated SOD1G37R mice was 397 days (n =8) compared with controls (379 days; n =8) (p <0.01, a difference of 18 days; Fig. 1B). Furthermore, treatment with WA significantly delayed the loss of motor function observed in the motor function tests and prevented the loss of body weight (Fig. 1C, D).Fig. 1

Bottom Line:
Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality.These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

ABSTRACTApproximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that Withaferin A (WA), an inhibitor of nuclear factor-kappa B activity, was efficient in reducing disease phenotype in a TAR DNA binding protein 43 transgenic mouse model of ALS. These findings led us to test WA in mice from 2 transgenic lines expressing different ALS-linked SOD1 mutations, SOD1(G93A) and SOD1(G37R). Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice. The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality. Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter. These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.